Pronunciation:

es-tra-DYE-ol

Brand Names:

• Estrace
• Estring
• Femring
• Imvexxy
• Vagifem

Dosage Forms:

• Insert, Extended Release
• Capsule, Liquid Filled
• Cream
• Tablet

Warnings:

Estrogen Alone TherapyEndometrial Cancer - There is an increased risk of cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding .Cardiovascular Disorders and Probable Dementia - The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone, relative to placebo .Cardiovascular Disorders and Probable Dementia - The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women .Cardiovascular Disorders and Probable Dementia - Do not use estrogen and progestin therapy for the prevention of cardiovascular disease or dementia .Cardiovascular Disorders and Probable Dementia - Only daily oral 0.625 mg CE was studied in the estrogen -alone substudy of the WHI. Therefore, thee relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile .Cardiovascular Disorders and Probable Dementia - In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.Cardiovascular Disorders and Probable Dementia - Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman .Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable Dementia - The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with combined medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo .Cardiovascular Disorders and Probable Dementia - The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women .Cardiovascular Disorders and Probable Dementia - Do not use estrogen and progestin therapy for the prevention of cardiovascular disease or dementia .Breast Cancer - The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer .Breast Cancer - Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile .Breast Cancer - Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman .

Use of unopposed estrogens increases the risk of endometrial cancer, while addition of a progestin decreases the risk of endometrial hyperplasia. Rule out malignancy if abnormal vaginal bleeding develops. Do not use estrogen alone or in combination with progestin to prevent cardiovascular disease or dementia. There is an increased risk of cardiovascular disorders (ie, DVT, pulmonary embolism, stroke, myocardial infarction) with combination therapy in women 50 years or older, and an increased risk of dementia in women 65 years or older with estrogen monotherapy or combination therapy. Combination therapy also increases the risk of invasive breast cancer. Prescribe estrogens with or without progestins at the lowest effective dose and for the shortest duration consistent with risks and treatment goals .

Classifications:

Therapeutic—

Female Reproductive Agent

Pharmacologic—

Estrogen

Uses of This Medicine:

Estradiol vaginal gel, insert, and ring are used to treat changes in and around the vagina (such as vaginal dryness, itching, and burning) caused by low estrogen levels or menopause.

Estradiol vaginal gel and ring are also used to treat moderate to severe hot flashes and other symptoms of menopause or low amounts of estrogen. The hormone from the vaginal gel or ring is absorbed through your vagina. It works by preventing symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (hot flashes) in women during menopause.

Estradiol vaginal insert is also used to treat moderate to severe painful sexual intercourse caused by menopause.

This medicine is available only with your doctor's prescription.

Before Using This Medicine:

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies—

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Children—

Appropriate studies have not been performed on the relationship of age to the effects of estradiol vaginal gel, insert, or ring in the pediatric population. Use of estradiol vaginal gel, insert, or ring is not indicated for use in children.

Older adults—

Although appropriate studies on the relationship of age to the effects of estradiol vaginal gel, insert, or ring have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have breast cancer, strokes, or dementia, which may require caution in patients receiving estradiol vaginal gel, insert, or ring.

Breast-feeding—

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Other medicines—

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Tranexamic Acid

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abametapir
• Amifampridine
• Amoxicillin
• Ampicillin
• Amprenavir
• Apalutamide
• Aprepitant
• Armodafinil
• Artemether
• Bacampicillin
• Belzutifan
• Betamethasone
• Bexarotene
• Bosentan
• Bupropion
• Carbamazepine
• Carbenicillin
• Cefaclor
• Cefadroxil
• Cefdinir
• Cefditoren
• Cefixime
• Cefpodoxime
• Cefprozil
• Ceftazidime
• Ceftibuten
• Cefuroxime
• Cenobamate
• Ceritinib
• Clarithromycin
• Clobazam
• Cloxacillin
• Colesevelam
• Conivaptan
• Cosyntropin
• Cyclacillin
• Cyclosporine
• Dabrafenib
• Darunavir
• Dexamethasone
• Dicloxacillin
• Donepezil
• Doxycycline
• Efavirenz
• Elagolix
• Elvitegravir
• Enasidenib
• Encorafenib
• Enzalutamide
• Eslicarbazepine Acetate
• Etravirine
• Fedratinib
• Fexinidazole
• Fosamprenavir
• Fosaprepitant
• Fosnetupitant
• Fosphenytoin
• Griseofulvin
• Guar Gum
• Isotretinoin
• Itraconazole
• Ivosidenib
• Lesinurad
• Lixisenatide
• Lorlatinib
• Lumacaftor
• Mavacamten
• Meropenem
• Minocycline
• Mitapivat
• Mitotane
• Mobocertinib
• Modafinil
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nafcillin
• Nelfinavir
• Netupitant
• Nevirapine
• Octreotide
• Oxacillin
• Oxcarbazepine
• Oxytetracycline
• Penicillin G
• Penicillin G Procaine
• Penicillin V
• Phenobarbital
• Phenylbutazone
• Phenytoin
• Pitolisant
• Pixantrone
• Prednisolone
• Prednisone
• Primidone
• Repotrectinib
• Rifabutin
• Rifampin
• Rifapentine
• Ritonavir
• Rufinamide
• Secobarbital
• Somatrogon-ghla
• St John's Wort
• Sugammadex
• Sultamicillin
• Tazemetostat
• Telaprevir
• Tetracycline
• Theophylline
• Ticarcillin
• Tigecycline
• Tirzepatide
• Tizanidine
• Topiramate
• Ulipristal
• Valproic Acid

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir
• Diazepam
• Ginseng
• Lamotrigine
• Levothyroxine
• Licorice
• Lorazepam
• Selegiline
• Tacrine
• Temazepam
• Tipranavir
• Triazolam
• Troleandomycin
• Voriconazole
• Warfarin

Other interactions—

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine

Other medical problems—

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Blood clots (eg, deep vein thrombosis, pulmonary embolism), active or history of or
• Breast cancer, known or suspected, or a history of or
• Heart attack, active or history of or
• Liver disease or
• Protein C, protein S, or other known blood clotting disorders or
• Stroke, active or history of or
• Surgery with a long period of inactivity or
• Tumors (estrogen-dependent), known or suspected—Should not be used in patients with these conditions.

• Angioedema or anaphylaxis—Should not be used in patients who have experienced these conditions with previous use of estradiol vaginal ring and insert.

• Asthma or
• Cancer, history of or
• Diabetes or
• Edema (fluid retention or body swelling) or
• Endometriosis or
• Epilepsy (seizures) or
• Gallbladder disease or
• Hereditary angioedema (swelling of the face, lips, tongue, or throat) or
• Hypercalcemia (high calcium in the blood) or
• Hypertension (high blood pressure) or
• Hypertriglyceridemia (high triglycerides or fats in the blood) or
• Hypocalcemia (low calcium in the blood) or
• Hypothyroidism (an underactive thyroid) or
• Jaundice during pregnancy or from using hormonal therapy in the past or
• Liver tumors or
• Migraine headache or
• Porphyria (an enzyme problem) or
• Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.

Proper Use of This Medicine:

It is very important that you use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects.

This medicine is to be used only in the vagina. Use it at bedtime unless your doctor tells you otherwise.

This medicine comes with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

To use the vaginal ring:

• This medicine is contained in a ring that you or your caregiver will put into your vagina. The ring will slowly release small amounts of medicine for your body to absorb. Your caregiver will show you how to insert the ring.
• Do not remove the ring from the sealed pouch until you are ready to use it.
• Once the ring is in place inside your vagina, you should not be able to feel it. If you feel uncomfortable, the ring may not be inserted far enough. Gently push the ring farther into your vagina. If you feel pain, talk to your doctor.
• You will leave the ring inside for 90 days (3 months), unless your doctor tells you a different schedule. After that time, remove the ring and insert a new one. If you forget to remove the ring after 90 days, call your doctor for instructions.
• The ring may move down into the lower part of your vagina accidently. This can happen if you strain to have a bowel movement. Use your finger to gently push the ring back into place. If the ring comes all the way out of your vagina, rinse it off with warm water and put it back in. Call your doctor if the ring comes out several times.
• If you need to remove the ring, hook your finger through the ring and pull it out.

To use the Imvexxy™ vaginal insert:

• The insert should be used only in your vagina. Do not swallow.
• Keep your hands clean and dry while handling the insert.
• Push an insert through the foil of the blister package and hold it with the larger end between your fingers.
• You may choose to put the insert into your vagina using the lying down or standing up position. Put the insert about 2 inches into your vagina, with the smaller end up, using your finger.
• Most women will start by using a new insert every day for two weeks, then change to using a new insert only 2 days each week. Carefully follow the schedule that your health caregiver tells you to.

To use the Vagifem® vaginal insert:

• The tablet should be used only in your vagina. Do not swallow the tablet.
• Each vaginal tablet comes packaged inside an applicator. Do not take the tablet out of the applicator. If the tablet comes out of the applicator but has not fallen out of the package, carefully put it back into the applicator for insertion. If the tablet falls out of the applicator, throw it away and use a new applicator that still has the tablet inside it.
• Keep your hands clean and dry while handling the tablet.
• Take the applicator out of the plastic wrap before using it.
• Use the applicator only one time and then throw it away. Use a new applicator for each dose.
• Most women will start by inserting a new tablet every day for two weeks, then change to inserting a new tablet only 2 days each week. Carefully follow the schedule that your health caregiver tells you to.

To use the Divigel®:

• Open the packet and use the entire contents of a packet on the skin of either right or left upper thigh once a day.
• Apply the gel to the right or left upper thigh on alternate days to avoid potential skin irritation.
• Do not apply the gel on the face, breasts, or irritated skin or in or around the vagina.
• Allow the gel to dry after application before dressing. Avoid fire, flame, or smoking until the gel has dried.
• Do not wash the application site within 1 hour after applying the gel.
• Avoid getting the gel into your eyes. Wash your hands after each application.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine. Grapefruit and grapefruit juice may change the amount of this medicine that is absorbed in the body.

Dosing—

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For vaginal dosage form (gel):
  • For atrophic vaginitis, hot flashes, and other symptoms caused by menopause:
    • Adults—At first, 0.25 grams applied on the skin of either right or left upper thigh once a day. Your doctor may adjust your dose as needed up to a maximum of 1.25 grams once a day.
    • Children—Use is not recommended.
• For vaginal dosage form (ring):
  • For atrophic vaginitis, hot flashes, and other symptoms caused by menopause:
    • Adults—One vaginal ring inserted into the vagina for 3 months. Your doctor may adjust your dose as needed.
    • Children—Use is not recommended.
• For vaginal dosage form (insert):
  • For treatment of atrophic vaginitis caused by menopause:
    • Adults—10 micrograms (mcg) or one insert into the vagina once a day for 2 weeks, followed by one insert 2 times a week.
    • Children—Use is not recommended.
  • For treatment of painful sexual intercourse caused by menopause:
    • Adults—At first, 4 micrograms (mcg) or one insert into the vagina once a day for 2 weeks, followed by one insert 2 times a week (every 3 to 4 days). Your doctor may adjust your dose as needed.
    • Children—Use is not recommended.

Missed dose—

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage—

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Wrap the used vaginal ring in tissue or toilet paper and throw it in the trash can. Do not flush it down the toilet.

Precautions While Using This Medicine:

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. These visits may be every 3 to 6 months. Pelvic exam, breast exam, and mammogram (breast x-ray) may be needed to check for unwanted effects, unless your doctor tells you otherwise. Be sure to keep all appointments.

It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using this medicine while you are pregnant could harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

Using this medicine over a long period of time may increase your risk of breast cancer, endometrial cancer, or uterine cancer. Talk with your doctor about this risk. If you still have your uterus (womb), ask your doctor if you should also use a progestin medicine. Check with your doctor immediately if you experience abnormal vaginal bleeding.

Using this medicine may increase your risk of dementia, especially in women 65 years of age and older.

Using this medicine may increase your risk for having blood clots, strokes, or heart attacks. This risk may continue even after you stop using the medicine. Your risk for these serious problems is even greater if you have high blood pressure, high cholesterol in your blood, diabetes, or if you are overweight or smoke cigarettes. Contact your doctor immediately if you experience chest pain, confusion, difficulty speaking, double vision, headaches, an inability to move arms, legs or facial muscle, or an inability to speak.

Tell the medical doctor or dentist in charge that you are using this medicine before any kind of surgery (including dental surgery) or emergency treatment. Your doctor will decide whether you should continue using this medicine. This medicine may also affect the results of certain medical tests.

Check with your doctor immediately if severe headache or sudden loss of vision or any other change in vision occurs while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Tell your doctor about any problems with your vagina, (eg, having an unusually shaped or narrow vagina). Tell your doctor if you have problems with your reproductive organs, bladder, rectum, or pelvic area.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Side Effects of This Medicine:

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common

Vaginal yeast infection

Incidence not known

Change in vaginal discharge

clear or bloody discharge from the nipple

decrease in the amount of urine

dimpling of the breast skin

fast heartbeat

fever

hives, itching, or rash

hoarseness

inverted nipple

irritation

joint pain, stiffness, or swelling

lump in the breast or under the arm

noisy, rattling breathing

pain or feeling of pressure in the pelvis

pain, redness, or swelling in the arm or leg

persistent crusting or scaling of the nipple

redness of the skin

redness or swelling of the breast

sore on the skin of the breast that does not heal

swelling of the eyelids, face, fingers, lips, hands, feet, or lower legs

tightness in the chest

troubled breathing at rest

troubled breathing or swallowing

vaginal bleeding

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Dizziness

drowsiness

nausea

stomach pain

tenderness of the breasts

unusual tiredness or weakness

vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Back pain

headache

itching or pain of the vagina or genital area

thick, white vaginal discharge with mild or no odor

weight gain

Less common

Body aches or pain

chills

cough

diarrhea

ear congestion

loss of voice

nasal congestion

runny nose

sneezing

sore throat

Incidence not known

Feeling sad or empty

headache, severe and throbbing

irritability

lack of appetite

tiredness

trouble concentrating

trouble sleeping

welts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.